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Page 628 Laubach et al. Cancer Drug Resist 2023;6:611-41 https://dx.doi.org/10.20517/cdr.2023.60

sterol synthesis [Figure 3]. Bioinformatics approaches have identified a negative correlation between SQLE
expression in human pancreatic adenocarcinoma and immune cell infiltration and immunotherapy
[237]
response , prompting the need for further validation of this potential target. While the intersection of
tumor-mediated cholesterol metabolism and ICB response is not as robust as other metabolic programs,
these recent studies hint at how this relationship can be exploited to overcome ICB resistance.

Fatty acids
Similar to cholesterol, FAs have a variety of cellular functions, including cell membrane formation through
phospholipids, energy metabolism, and precursors for signaling lipids [Figure 3]. Intracellular FA
abundance is regulated by import through CD36 or FA transport proteins and synthesis via fatty acid
[238]
synthase (FASN) from acetyl-CoA or malonyl-CoA . FAs undergo modifications to chain length to form
long-chain FAs (LCFAs) or very long-chain FAs (VLCFAs) and saturation to form mono-, di-, and poly-
unsaturated FAs. Saturation and chain length dictate FA function and their role in oncogenesis . In
[239]
energy metabolism, FAs are subject to fatty acid b-oxidation (FAO) in the mitochondria to generate FADH,
[240]
NADH, and acetyl-CoA to fuel a variety of energetic processes .

The increased demand for FAs in malignant cells sustains their rapid proliferation by serving as an energy
source via FAO and as an indispensable component for cell membrane formation. Moreover, certain FAs
are important precursors for a variety of oncogenic signaling mediators [241-243] . To meet these metabolic
demands, cancer cells will increase the uptake and synthesis of fatty acids, while also inducing lipolysis of
neighboring adipocytes [244-248] . Continuous evidence is emerging that altered FA metabolism by tumor cells
alters the lipidome in the TIME, contributing to CD8 T cell dysfunction. However, the effect of tumor-
+
derived FA metabolic alterations on ICB resistance is not well-studied.

Malignant cells exploit the increased lipid availability in patients with obesity and remodel the TIME to
inhibit CD8 T cell function and promote cancer growth. High-fat diet-induced obesity in multiple mouse
+
models of cancer alters the metabolic profile of malignant cells to increase FA uptake and utilization and
creates an immunosuppressive TIME that inhibits CD8 T cell infiltration and function . Moreover,
[249]
+
+
inhibiting obesity-induced metabolic rewiring in murine colorectal carcinoma tumors restores CD8 TIL
function and increases anti-tumor immune function . Mechanistically, researchers found that CD8 T
+
[249]
cells in obesity-associated breast cancer tumors exhibit ligation of leptin and PD-1 to reduce effector
functions through activation of STAT3, which promotes FAO and inhibits glycolysis . PD-1 ligation also
[250]
promotes FAO in T cells through upregulation of carnitine palmitoyltransferase 1A (CPT1A), an essential
[251]
enzyme involved in FAO . Further, obesity in mice, humans, and non-human primates leads to increased
PD-1 expression and CD8 T cell exhaustion . These data are consistent with the notion that CD8 T cells
+
[252]
+
exhibit a shift from glycolysis to FAO as they become exhausted, highlighting the need to further explore
targeting metabolic reprogramming as a way to reinvigorate CD8 T cells and abate ICB resistance.
+
+
Similar to obese models of cancer, non-obese models show that CD8 T cell function is inhibited by an
overabundance of FAs within the TIME. In response to excess lipid content within the TIME, CD8 TILs
+
[205]
exhibit increased intracellular lipid levels compared to peripheral CD8 T cells . Exhaustion in CD8 TILs
+
+
is characterized by the expression of CD36, which imports oxidized low-density lipoproteins, oxidized
phospholipids, and long-chain fatty acids . Increased uptake of oxidized low-density lipoproteins
[205]
+
promotes lipid peroxidation in CD8 TILs, leading to decreased cytokine production and effector
function . Moreover, the accumulation of VLCFAs within the TIME drives the uptake of LCFAs in CD8
[205]
+
T cells, and instead of serving as an energy source, they promote mitochondrial dysfunction, lipotoxicity,
and exhaustion . Like cancer cells, immunosuppressive cells, such as Tregs, macrophages, and MDSCs,
[253]